An essential task for the central auditory pathways is to parse the auditory messages sent by the two cochleae into auditory objects, the segregation and localisation of which constitute an important means of separating target signals from noise and competing sources. When hearing losses are too asymmetric, the patients face a situation in which the monaural exploitation of sound messages significantly lessens their performance compared to what it should be in a binaural situation. Rehabilitation procedures must aim at restoring as many binaural advantages as possible. These advantages encompass binaural redundancy, head shadow effect and binaural release from masking, the principles and requirements of which make up the topic of this short review. Notwithstanding the complete understanding of their neuronal mechanisms, empirical data show that binaural advantages can be restored even in situations in which faultless symmetry is inaccessible.

In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre;Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes. Coordination of the left and right sides of the body requires the action of neurons whose axons cross the nervous system midline. The precise contributions of “commissural” neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels. A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations. This led to disruption of specific commissures in the sensory, motor, and sensorimotor systems, and resulted in severe but specific functional deficits. Surprisingly, although rerouted axons do not cross the midline, they still project to their appropriate neuronal targets, suggesting that midline crossing is not required to complete the axonal guidance program of those neurons. Moreover, some of the mouse lines represent good models for human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS), which is characterized by deficits in coordinated eye movements. This study links defects in commissural axon guidance with specific and dramatic behavioral phenotypes.

Gjb2andGjb6,two contiguous genes respectively encoding the gap junction protein connexin26 (Cx26) and connexin 30 (Cx30) display overlapping expression in the inner ear. Both have been linked to the most frequent monogenic hearing impairment, the recessive isolated deafness DFNB1. Although there is robust evidence for the direct involvement of Cx26 in cochlear functions, the contribution of Cx30 is unclear since deletion ofCx30strongly downregulatesCx26both in human and in mouse. Thus, it is imperative that any role of Cx30 in audition be clearly evaluated. Here, we developed a newCx30knock-out mouse model (Cx30^Δ/Δ) in which half ofCx26expression was preserved. Our results show thatCx30andCx26coordinated expression is dependent on the spacing of their surrounding chromosomic region, and thatCx30^Δ/Δmutants display normal hearing. Thus, in deaf patients withGJB6deletion as well as in the previousCx30knock-out mouse model, defectiveCx26expression is the likely cause of deafness, and in contrast to current opinion, Cx30 is dispensable for cochlear functions.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1^N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy. Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.